Inhibitors of bruton's tyrosine kinase

Abstract

Described herein are kinase inhibitor compounds of Formula IV: wherein R b , R 6 , T, Y, and Z are defined herein. Also described herein are methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.

What is claimed is: 
     
       1. A compound having the structure of Formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein:
 T is a bond; 
 Y and Z together with the carbon atom to which they are attached form a C 2 -C 10 heterocycloalkyl, optionally substituted with at least one X; 
 wherein when Y and Z together with the carbon atom to which they are attached form a nitrogen atom-containing C 2 -C 10 heterocycloalkyl the nitrogen atom of the C 2 -C 10 heterocycloalkyl is substituted with W and the carbon atoms of the C 2 -C 10 heterocycloalkyl are optionally substituted with at least one X; 
 W is selected from C(═O)O-J, C(═O)NR 2 -J, C(═NR 2 )-J, —C(═NR 2 )NR 2 -J, C(═N—OR 3 )-J, C(═S)-J, S(═O) v -J, S(═O) v O-J; 
 X is F, Cl, Br, I, —CN, —NO 2 , —OR 3 , —N(R 2 ) 2 , —SR 2 , —C 1 -C 6 alkyl, —C(═O)R 2 , —OC(═)R 2 , —NR 2 C(═O)N(R 2 ) 2 , —C(═O)N(R 2 ) 2 , —C(═NR 2 )N(R 2 ) 2,  —C(═N—OR 2 )N(R 2 ) 2,  —C(═S)R 2 , —S(═O) v R 2 , —OS(═O) v R 2 , —NR 2 C(═O)OR 2 , —NR 2 S(═O) v R 2 ; 
 J is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl optionally substituted with at least one R 1 ; 
 v is 1 or 2; 
 R b  is NH 2 ; 
 R 1  is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —NR 2 C(═O)R 8 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —OC(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , and —SO 3 H; 
 R 2  is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 3 -C 6 cycloalkyl; 
 R 3  is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or SO 3 H; 
 each R 6  is independently selected from H, —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, —NR 2 S(═O) 2 R 2 , —S(═O) 2 N(R 2 ) 2 , —C(═O)CF 3 , —C(═O)NR 2 S(═O) 2 R 2 , —S(═O) 2 NR 2 C(═O)R 2 , —N(R 2 ) 2 , wherein optionally the two R 2  groups of N(R 2 ) 2  and the nitrogen atom to which they are attached form a C 2 -C 6  heterocycloalkyl ring, —NR 2 C(═O)R 2 , —NR 2 C(═O)N(R 2 ) 2 , —CO 2 R 2 , —C(═O)R 2 , —OC(═O)R 2 , —C(═O)N(R 2 ) 2 , —OS(═O) 2 R 2 , —OS(═O) 2 OR 2 , —S(═O)R 2 , —S(═O) 2 R 2 , and —SO 3 H, wherein at least one R 6  is —OH; 
 R 8  is an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, or an optionally substituted C 3 -C 6 cycloalkyl; or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. The compound of  claim 1  wherein W is C(═O)J. 
     
     
       3. The compound of  claim 2  wherein J is substituted with at least one R 1 . 
     
     
       4. The compound of  claim 3  wherein R 1  is selected from F, Cl, Br, I, —CN, —NO 2 , —SR 2 , —OR 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl. 
     
     
       5. The compound of  claim 2  wherein Y and Z together with the carbon atom to which they are attached form a nitrogen atom-containing C 2 -C 10 heterocycloalkyl selected from: 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 5  wherein C 2 -C 10 heterocycloalkyl is 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1  wherein J is substituted with one R 1 . 
     
     
       8. The compound of  claim 1  wherein J is substituted with two R 1 . 
     
     
       9. The compound of  claim 7  wherein R 1  is selected from F, Cl, Br, I, —CN, and —OR 3 . 
     
     
       10. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
       11. The compound of  claim 6  wherein C 2 -C 10 heterocycloalkyl is 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 11  wherein J is ethyl optionally substituted with at least one R 1 ; and R 1  is selected from F, Cl, Br, I, —CN, —SR 2 , and —OR 3 . 
     
     
       13. The compound of  claim 12  wherein J is unsubstituted ethyl. 
     
     
       14. The compound of  claim 12  wherein J is —CH(OH)CH 2 (OH).